Cyclosporines are a group of nonpolar cyclic oligopeptides, which have a broad spectrum of useful pharmacological activities, particularly immuno-suppressive activity and anti-inflammatory activity. The major cyclosporine metabolite is cyclosporine A. Cyclosporine A is a neutral, lipophilic, cyclic endecapeptide with a low aqueous solubility and a molecular weight of 1200 daltons.
Cyclosporine inhibits T cell activation and causes suppression of cell-mediated immune response. Cyclosporine has been used for suppression of immunological responses caused by tissue and organ transplantation, for example, transplantation of the heart, lung, liver, kidney, pancreas, bone marrow, skin and cornea, and especially the transplantation of foreign tissues and organs. In addition, cyclosporine is useful for the suppression of hematological disorders such as anemia, various autoimmune diseases such as systemic lupus erythematosus and idiopathic malabsorption syndrome, and inflammatory diseases such as arthritis and rheumatoid disorders. Cyclosporine is also useful in treatment of protozoal diseases such as malaria and schistosomiasis, and has recently been used in chemotherapy.
Cyclosporine is highly lipophilic and hydrophobic. Therefore, cyclosporine is sparingly soluble in water, and well dissolved in an organic solvent such as methanol, ethanol, acetone, ether, chloroform and the like. Due to the low water-solubility of cyclosporine having the above-mentioned properties, when cyclosporine is administered orally, its bioavailability is extremely low and may be greatly influenced by the conditions of each individual patient. Accordingly, it is very difficult to retain an effective therapeutic concentration. Moreover, cyclosporine may show considerable side effects such as nephrotoxicity. Thus, cyclosporine is very difficult to formulate into a preparation for oral administration due to its low water solubility. Accordingly, numerous studies have been extensively conducted to discover a preparation suitable for the effective oral administration of cyclosporine, which can provide a suitable uniform dosage and appropriate bioavailability.
Previously, the preparations suitable for oral administration of sparingly water-soluble cyclosporine have usually been formulated in the form of an emulsion or microemulsion pre-concentrate (Table 1). Such formulations are commercially available under the names ‘Sandimmune’ and ‘Neoral.’ Both formulations are available in solution for oral use or in soft gelatin capsules. The ‘Sandimmune’ formulation contains cyclosporine in olive oil with the surfactant Labrafil. However, the resulting liquid formulation is administered as an aqueous dilution which makes it very difficult to adapt the subject to its administration and to provide a uniform dosage for oral administration.
The ‘Neoral’ formulation is a microemulsion pre-concentrate which contains cyclosporine in an anhydrous oily vehicle, medium chain triglycerides, surfactants, glycerol and alcohol.
Another commercially available cyclosporine formulation is marketed under the tradename ‘SangCya’. ‘SangCya’ is a formulation of cyclosporine, the surfactant Tween 80, ethanol, and glycols. Upon dilution, ‘SangCya’ forms droplet sizes between 200 to 300 nm, which may represent a micellar solution. Recently, however, studies indicate that ‘SangCya’ has a lower bioavailability upon dilution than other commercially available cyclosporine formulations.
TABLE 1Comparison of Various Cyclosporine FormulationsFormulationPhysical StateDroplet SizeSandimmunePrecipitate  2-5 μmNeoralMicroemulsion 30-50 nmSangCyaMicellar solution200-300 nm